title: The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation.
abstract: OBJECTIVE
  Macrophages (M) are one of the most important cells of the innate immune system for first line defense. Upon transplantation (Tx), M play a prominent role during lung ischaemia reperfusion (I/R) injury. Here, we hypothesize that the depletion of donor M ameliorates the post-transplant lung I/R injury.
  
  
  METHODS
  Orthotopic single-lung Tx was performed between syngeneic BALB/c mice after a cold ischaemic time of 8 h and a reperfusion time of 10 h. Prior to graft implantation, alveolar macrophages of donor lungs were selectively depleted applying the 'suicide technique' by intratracheal application of clodronate liposomes (experimental, n = 6) vs the application of empty liposomes (control, n = 6). Cell count (number of F4/80(+)-macrophages) and graft injury were evaluated by histology and immunohistochemistry, and levels of lactat dehydrogenase (LDH) (apoptosis assay), enzyme linked immunosorbent assay for nuclear protein high-mobility-group-protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α) and transforming growth factor beta1 (TGF-β1) in plasma were analysed.
  
  
  RESULTS
  Clodronate liposomes successfully reduced 70% of M from donor lungs when compared with grafts treated with empty liposome only. M-depleted transplants showed improved histology and revealed considerably less graft damage when compared with control recipients (LDH, P = 0.03; HMGB1, P = 0.3). Oxygenation capacity was ameliorated in M-depleted transplants, if not significant (P = 0.114); however, wet/dry ratio did not differ between groups (P = 0.629). The inflammatory response was significantly reduced in M-depleted mice when compared with control recipients (TNF-α, P = 0.042; TGF-β1, P = 0.039).
  
  
  CONCLUSIONS
  The selective depletion of M in donor lung transplants can be successfully performed and results in a sustained anti-inflammatory response upon I/R-injury. The beneficial effect of this preconditioning method should be further evaluated as a promising tool for the attenuation of I/R prior to graft implantation in clinical Tx.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tsushima
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yamada
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
mesh_terms: D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage; D008168:Lung / Q000166:cytology; D016040:Lung Transplantation / Q000009:adverse effects / Q000379:methods*; D016676:Macrophages, Alveolar / Q000166:cytology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015427:Reperfusion Injury / Q000517:prevention & control*; D019737:Transplants
chemical_list: D016207:Cytokines; D008081:Liposomes; D004002:Clodronic Acid
keywords: Ischaemia-reperfusion injury; Lung; Macrophage depletion; Mouse; Transplantation